Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility.

ABSTRACT: Maintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca²⁺ buffering and spare respiratory capacity. Bi-directional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate s

SUBMITTER: Styr B 

PROVIDER: S-EPMC6559804 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature